Structural Changes Fundamental to Gating of the Cystic Fibrosis Transmembrane Conductance Regulator Anion Channel Pore

2016 ◽  
pp. 13-32 ◽  
Author(s):  
Paul Linsdell
Keyword(s):  
Cystic Fibrosis ◽  
Structural Changes ◽  
Anion Channel ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Channel Pore ◽  
Cystic Fibrosis Transmembrane

scholarly journals The Pore Architecture of the Cystic Fibrosis Transmembrane Conductance Regulator Channel Revealed by Co-Mutation in Pore-Forming Transmembrane Regions

2016 ◽  
pp. 505-515
Author(s):  
F. QIAN ◽  
L. LIU ◽  
Z. LIU ◽  
C. LU
Keyword(s):  
Cystic Fibrosis ◽  
Single Channel ◽  
Transmembrane Conductance Regulator ◽  
Patch Clamp Recording ◽  
Transmembrane Conductance ◽  
Channel Pore ◽  
Selective Filter ◽  
Transmembrane Regions ◽  
Cystic Fibrosis Transmembrane ◽  
Insight Into

The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel contains 12 transmembrane (TM) regions that are presumed to form the channel pore. However, there is no direct evidence clearly illustrating the involvement of these transmembrane regions in the actual CFTR pore structure. To obtain insight into the architecture of the CFTR channel pore, we used patch clamp recording techniques and a strategy of co-mutagenesis of two potential pore-forming transmembrane regions (TM1 and TM6) to investigate the collaboration of these two TM regions. We performed a range of specific functional assays comparing the single channel conductance, anion binding, and anion selectivity properties of the co-mutated CFTR variants, and the results indicated that TM1 and TM6 play vital roles in forming the channel pore and, thus, determine the functional properties of the channel. Furthermore, we provided functional evidence that the amino acid threonine (T338) in TM6 has synergic effects with lysine (K95) in TM1. Therefore, we propose that these two residues have functional collaboration in the CFTR channel pore and may collectively form a selective filter.

scholarly journals Structural comparative modeling of multi-domain ΔF508 CFTR

2021 ◽  
Author(s):  
Eli Fritz McDonald ◽  
Hope Woods ◽  
Shannon Smith ◽  
Minsoo Kim ◽  
Clara T. Schoeder ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Rational Design ◽  
Anion Channel ◽  
Comparative Modeling ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Binding Domains ◽  
Δf508 Cftr ◽  
Domain Models ◽  
Cystic Fibrosis Transmembrane

Cystic Fibrosis (CF) is a common genetic disease caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), an epithelial anion channel expressed in several vital organs. Absence of functional CFTR results in imbalanced osmotic equilibrium and subsequent mucus build up in the lungs - which increases the risk of infection and eventually causes death. CFTR is an ATP binding cassette (ABC) transporter composed of two transmembrane domains (TMDs), two nucleotide binding domains (NBDs), and an unstructured regulatory domain. The most prevalent patient mutation is the deletion of F508 (ΔF508), making ΔF508 CFTR the primary target for current FDA approved CF therapies. However, no experimental multi-domain ΔF508 CFTR structure has been determined and few studies have modeled ΔF508 using multi-domain WT CFTR structures. Here, we used cryo-EM density data and Rosetta comparative modeling (RosettaCM) to compare a ΔF508 model with published experimental data on CFTR NBD1 thermodynamics. We then apply this modeling method to generate multi-domain WT and ΔF508 CFTR structural models. These models demonstrate the destabilizing effects of ΔF508 on NBD1 and the NBD1/TMD interface in both the closed and open conformation of CFTR. Furthermore, we modeled ΔF508/R1070W and ΔF508 bound to a the CFTR corrector VX-809. Our models reveal the stabilizing effects of R1070W and VX-809 on multi-domain models of ΔF508 CFTR and pave the way for rational design of additional drugs that target ΔF508 CFTR for treatment of CF.

scholarly journals Molecular structure of the ATP-bound, phosphorylated human CFTR

2018 ◽  
Vol 115 (50) ◽  
pp. 12757-12762 ◽  
Author(s):  
Zhe Zhang ◽  
Fangyu Liu ◽  
Jue Chen
Keyword(s):  
Molecular Structure ◽  
Cystic Fibrosis ◽  
Conformational Changes ◽  
Anion Channel ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Common Features ◽  
Proper Functions ◽  
Cystic Fibrosis Transmembrane ◽  
Kinase A

The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel important in maintaining proper functions of the lung, pancreas, and intestine. The activity of CFTR is regulated by ATP and protein kinase A-dependent phosphorylation. To understand the conformational changes elicited by phosphorylation and ATP binding, we present here the structure of phosphorylated, ATP-bound human CFTR, determined by cryoelectron microscopy to 3.2-Å resolution. This structure reveals the position of the R domain after phosphorylation. By comparing the structures of human CFTR and zebrafish CFTR determined under the same condition, we identified common features essential to channel gating. The differences in their structures indicate plasticity permitted in evolution to achieve the same function. Finally, the structure of CFTR provides a better understanding of why the G178R, R352Q, L927P, and G970R/D mutations would impede conformational changes of CFTR and lead to cystic fibrosis.

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